Marine phytopharmaceuticals

Marine Phytopharmaceuticals
Dr. Harshad Malve
MBBS, MD Pharmacology

A wide variety of environments

Biodiversity
• Oceans - most biodiverse environment with 34 of the 36
known phyla represented
• By comparison, the land has only 17 of the known Phyla!
• Genetic diversity translates to chemical diversity =
Promising new drugs
Malve H. Exploring the ocean for new drug developments: Marine pharmacology. J Pharm Bioall Sci 2016;8:83-91.

Sources of Marine drugs
 Sponges
 Coelenterates (sea whips, sea fans and soft corals)
 Tunicates
 Molluscs (nudibranchs, sea hares, etc.)
 Echinoderms (starfish, sea cucumbers, sea urchins,
sand dollars etc.)
 Bryozoans (moss animals)
 A wide variety of marine microorganisms

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Global Marine Pharmaceutical Market
2018-2022
Technavio report. Published March 2018

Marine Pharmacology
• Deals with investigation, identification & use of medically
important plants & animals, extracts or substances isolated
from marine organisms
• Estimated 75% of earth’s surface covered by water
• Research into the chemistry of marine organisms is
unexplored & represents a vast resource for new drugs

Development of Marine pharmacology

• Late 1970s: Marine drug discovery begun - marine plants
& animals were genetically & biochemically unique
• In the 1970's, in a survey of Caribbean invertebrates, the
impressive cytotoxic properties of extracts of mangrove
ascidian Ecteinascidia turbinata were discovered
• After 20 years of advancements in chemistry, the active
substances, named the ecteinascidins were isolated in
1990
Development of Marine pharmacology

Drugs of marine origin:

Ziconotide
• First drug of marine origin approved by
FDA on 31st December 2004
• A non-opioid, non-NSAID, non-local anaesthetic used for
amelioration of chronic pain
• Derived from the toxin of cone snail Conus magus
• Contains synthetic form of the cone snail peptide ω-
conotoxin
• Blocks the N-Type calcium channels on the primary
nociceptive nerves in the spinal cord

• Used only for “management of severe chronic pain”
• Approved for the treatment of chronic pain as a morphine
replacement therapy
• It is the most powerful painkiller known to date
• Must be administered intra-thecally
• Common side effects: dizziness, nausea, confusion &
headache
• Rare side effects: hallucinations, suicidal thoughts, new or
worsening depression, meningitis and seizures
Ziconotide

Anti-cancer candidates
• Trabectedin
• KLH
• Didemnin B
• Dolastatin 10
• Halichondrin B
• Bryostatin 1
• Aplidin (APL)
• Kahalalide F (KF)

Trabectedin (Ecteinascidin 743)
• A tetrahydroisoquinoline alkaloid produced by the tunicate
Ecteinascidia turbinata
• Chemically related to a rare group of microbial
antibiotics, the saframycins
• Induces a broad inhibition of activated transcription
with no effect on the constitutive transcription
• Dose limiting toxicities are bone marrow toxicity & fatigue

• EMEA & US FDA have granted orphan drug status for
treatment of patients with advanced soft tissue sarcoma
& ovarian cancer
• It is also undergoing clinical trials for the treatment of
breast, prostate, and paediatric sarcomas
Trabectedin (Ecteinascidin 743)

Keyhole Limpet Hemocyanin (KLH)
• Promising anti-cancer drug used as an immunotherapeutic
agent
• Copper containing extracellular respiratory protein present
in Megathura crenulata, a marine Gastropod species
• Possesses remarkable immunostimulatory properties in
experimental animals and human
• Used in experimental immunology and also clinically as an
immunotherapeutic agent
• Used in treatment of Urinary bladder carcinoma

Didemnin B
• Cyclodepsipeptide compounds isolated from a tunicate
(sea-squirt) Trididemhum solidum
• 1st isolated in 1978 at the University of Illinois
• A strong antiviral agent against both DNA and RNA viruses
like Herpes simplex virus type 1
Malve H. Exploring the ocean for new drug developments: Marine pharmacology. J Pharm
Bioall Sci 2016;8:83-91.

• A strong immunosuppressant that shows some potential
in skin graft
• Showed impressive cytotoxicity against lymphomas
• It has completed phase II human clinical trials against
adenocarcinoma of the kidney
Didemnin B

Dolastin-10 (Brentuximab vedotin)
• A pentapeptide derived from marine mollusk Dolabella
auricularia with potential antineoplastic activity
• Showed outstanding inhibitory effects against several
forms of skin cancers in laboratory studies
• Binding to tubulin, inhibits microtubule assembly, resulting
in formation of tubulin aggregates & inhibition of mitosis
• Also induces tumor cell apoptosis

Halichondrin B
• This metabolite was discovered in
marine sponge Halichondria okadai in 1985
• Highly potent cytotoxic agent
• Eribulin mesylate is a synthetic macrocyclic ketone
derivative of the marine natural product Halichondrin B
• Undergoing clinical trials for the treatment of advanced
and metastatic breast cancer

Bryostatin-1
• A macrolactone isolated from
marine bryozoan, Bugula neritina
• Modulates cell-signaling enzyme protein kinase C (PKC)
activity
• It inhibits the enzyme resulting in the inhibition of tumor
cell proliferation, the promotion of tumor cell
differentiation & the induction of tumor cell apoptosis

• Sensitizes cancer cells to cytotoxic effects of anti-cancer
agents & act synergistically with other chemotherapeutic
agents
• Also represent a pharmacological strategy for anti-dementic
& memory enhancement therapies
Bryostatin-1

Aplidin (APL / Pliditepsin)
• A cyclic depsipeptide isolated from the Mediterranean
tunicate Aplidium albicans
• Decreases the secretion of the Vascular Endothelial Growth
factor (VEGF) & expression of the VEGF-r1 receptor
• Induces apoptosis via activation of N-terminal kinase &
increases intracellular production of ROS & alters
mitochondrial membrane potential
• A remarkable lack of haematological toxicity

• 6th October, 2004: Orphan drug status by the US FDA for
the treatment of Multiple Myeloma (MM)
• FDA approved production process strategy of Aplidin(R),
as an Anti-tumor agent in 2008
Aplidin (Pliditepsin)

Kahalalide F (KF)
• Isolated from Hawaiian herbivorous marine mollusk Elysia
rufescens
• Potent cytotoxic activity in vitro against cell lines from solid
tumors including prostate, breast & colon carcinomas,
neuroblastoma, chondrosarcoma & osteosarcoma
• Mechanism of action is mostly unknown
• Seems to have the lysosomes as the cellular target
• Phase I trials showed safety of Kahalalide F in Prostate
Cancer patients however this drug was discontinued later

Anti-helmintics
• Amphilactams A–S
• Geodin A

Amphilactams A–S
• Macrocyclic lactone/lactams isolated from sponge
Amphimedon spp. showed anti-helmintic activity comparable
to that of existing anthelmintics like levamisole
• But the mechanism of action of these compounds was not
determined

Geodin A
• Geodin A Mg salt, was isolated from the sponge Geodia sp.
• Mechanism of action of the pure Geodin A was not
explored
• It occurs naturally as the Mg salt
• It was nematocidal to the nematode Haemonchus
contortus

Anti-bacterials
• Loloatins A–D
• Myticin
• Psammaplin A

Loloatins A–D
• Isolated from a marine bacterium
• Exhibited in vitro antimicrobial activity against methicillin-
resistant Staphylococcus aureus, vancomycin-resistant
enterococci & penicillin-resistant Streptococcus pneumoniae

Myticin
• Isolated from hemocytes & plasma of the mussel Mytilus
galloprovincialis
• Myticins A & B had marked activity against the Gram-
positive strains Micrococcus luteus, Bacillus megaterium &
Enterococcus viridans, other Gram-positive, Gram-negative
bacteria & fungi were unaffected

Psammaplin A
• Derived from sponge Psammaplysilla sp. possessed
antibacterial activity against methicillin-resistant Gram-
positive Staphylococcus aureus
• Discontinued after phase I

Anti-tubercular
• Monoterpenes
• Isolated from the marine red alga Plocamium hamatum
• One of them was anti-tubercular towards Mycobacterium
tuberculosis & Mycobacterium avium

Anti-fungals
• Bengazole, bengamide
• Oceanapiside
• Spongistatin I
• Tanikolide
• Theopederins F–J
Malve H. Exploring the ocean for new drug developments: Marine pharmacology.
J Pharm Bioall Sci 2016;8:83-91.

• The bengazole derivatives & a new bengamide obtained
from the sponge Pachastrissa sp
• The bengazole derivatives were observed to be active
against Candida albicans
• Oceanapiside, from the sponge Oceanapia phillipensis,
demonstrated antifungal activity against the fluconazole-
resistant yeast Candida glabrata
Anti-fungals

• Spongistatin 1 isolated from the sponge Hyrtios erecta
demonstrated potent microtubule-severing activity
• Tanikolide was isolated from the marine cyanobacterium
Lyngbia majuscula
• Theopederins F–J from the sponge Theonella swinhoei
• Theopederin-F was particularly effective against
Saccharomyces cerevisiae
Anti-fungals

• 15-a-Methoxy- puupehenol
• Isolated from the marine sponge Hyrtios sp.
• Demonstrated anti-malarial activity against chloroquine-
susceptible & chloroquine-resistant strains of P. falciparum
Anti-malarials

Anti-virals
• Lamellarin α-20-sulfate
• Papuamides A–D
• Polycitone A
• Glycosaminoglycan
• Sulfated β-galactan
• Poly-hydroxysteroids
• Sansalvamide

• Alkaloid lamellarin α 20-sulfate in an unidentified ascidian
showed selective in vitro inhibition of HIV integrase
• Papuamides A, B, C & D were isolated from the sponges
Theonella mirabilis & Theonella swinhoei
• Papuamides A & B inhibited the infection of human T-
lymphoblastoid cells by HIV-1 in vitro
Anti-virals

• Polycitone A isolated from the ascidian Polyctor sp., is a
potent inhibitor of reverse transcriptase of HIV & both C
and B retroviruses, as well as a general inhibitor of cellular
DNA polymerases
• Sulfated derivatives of a glycosaminoglycan isolated from
marine bacterium Pseudomonas sp. act against two strains of
influenza virus types A
Anti-virals

Anti-platelete agents
• Maitotoxin - extremely potent toxin produced by
Gambierdiscus toxicus
• A marine toxin causing ciguatera poisoning
• Mechanism of action was similar to
a thromboxane A receptor agonist
Malve H. Exploring the ocean for new drug developments: Marine pharmacology. J
Pharm Bioall Sci 2016;8:83-91.

Anti-Coagulants
• Sulfated fucans
• Derived from brown algae & echinoderm
• Highly branched sulfated fucans from brown algae directly
inhibit thrombin
• Linear fucans from echinoderms required the presence of
anti-thrombin or heparin cofactor II for inhibition of
thrombin

Anti-inflammatory
• Africanene,
• Cacospongiolide B,
• Palinurin, Palinurine A and B
• Plakotenin

Africanene
• Sesquiterpene africanene, isolated from the soft coral
Sinularia leptoclados
• It resulted in a more potent reduction of paw volume than
that produced by 100 mg/kg body weight of ibuprofen, in
carrageenan-induced rat edema assay

Cacospongionolide B
• A novel sesterterpene inhibitor of human synovial
phospholipase A2 isolated from the sponge Fasciospongia
cavernosa
• It irreversibly inhibited both secretory PLA2 in vitro and
group II secretory PLA2 in vivo

Palinurin, Palinurine A & B
• Isolated from the marine sponge Ircinia echinata
• Palinurin inhibits TXB2 & Oxide radicals
• Palinurine A and B are relatively ineffective inhibitors of
both TXB2 and Oxide radicals

Immunosuppressant
• Immunosuppressant activity was reported for the novel
glycolipids simplexides, isolated from the sponge Plakortis
simplex
• Showed a 43% inhibitory effect on lymph node cell
proliferation

Limiting factors
• Supply (sustainable, industrially feasible)
• Formulation (suitable for clinical use)
• Analytical method
• Preclinical pharmacokinetics
• Pharmacogenetics (metabolic pathway)
• Therapeutic index
• Toxicities

Measures to maintain supply
• Controlled & sustainable use of natural resources
• Mariculture: Favouring (by farming) the growth of the
organism in its natural milieu
• Aquaculture: Culture of the organism under artificial
conditions
• Hemi-synthesis: use of a parent/related compound as
starting point followed by a short/industrially effective
synthetic process
• Synthesis

Research institutes in India Courses available
1. National Institute of Oceanology
(NIO), Goa with regional centers at
Kochi, Mumbai and
Visakhapatnam
2. Central Salt & Marine Chemicals
Research Institute (CSMCRI),
Bhavnagar, Gujarat
3. Central Drug Research Institute
(CDRI), Lucknow
1. M.Sc. Marine Pharmacology at Chettinad
University, Kanchipuram, Tamilnadu
2. M.Sc. Marine Pharmacology, Annamalai
University, Tamilnadu
3. M.Sc. Marine Studies & Coastal Resource
Management, Madras Christian College,
Chennai, Tamilnadu
4. M.Sc. Marine Biotechnology, Goa University,
Goa

Global research institutes Courses available
1. The Roche Research Institute of
Marine Pharmacology, New South
Wales, Australia
2. Marine Biotechnology Centre,
University of California, Santa
Barbara, USA
3. Balunas Lab, University of
Connecticut, USA
1. Post graduate courses in marine biology,
Ocean College, Zhejiang University, China
2. Bachelor, Master and Doctoral programs in
Marine Pharmacy, China Pharmaceutical
University, Nanjing, China
3. M.Sc/Diploma Marine Biodiversity and
Biotechnology, Heriot Watt University,
Edinburgh, Scotland
4. Bachelor Program in Marine Biology, Heriot
Watt University, Edinburgh, Scotland

Thank You….!!!
Any queries?
Contact: 9820004598
dr.harshad.malve@gmail.com

Marine phytopharmaceuticals

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